Schizophrenia is a severe neuropsychiatric disorder with complex etiology that affects approximately 1% of the human population. There exists a critical need to understand the underlying etiology and pathophysiology of the disease in order to advance the development of novel therapeutics, particularly to target cognitive dysfunction. Recent genome-wide association and family-based studies have identified several copy number variants (CNVs) associated with schizophrenia. However, despite the strong genetic risk for schizophrenia associated with these CNVs, the etiologically relevant gene(s) in each of these genomic intervals remain unknown. There is therefore a pressing need for systematic and scalable strategies to gain insight into the function of genes associated with schizophrenia as well as other neuropsychiatric disorders. The overall goal of our current application is test the hypothesis that loss-of-function of specific genes within schizophrenia CNVs leads to a dysfunction in mechanisms regulating neuroplasticity. To test this hypothesis our proposal has 3 aims: 1. We will devise robust, high-throughput, image-based assays of neuroplasticity along with an integrated image analysis framework. 2. We will perform high-throughput, lentiviral short hairpin RNA (shRNA) screens of schizophrenia genes to identify regulators of neuroplasticity. 3. We will validate loss-of-function cellular and synaptic phenotypes of schizophrenia genes by performing more detailed, and higher resolution, morphological and functional analyses of candidate shRNAs using imaging and measures of basal and evoked synaptic transmission in cultured neurons and brain slices. It is our hope that the experiments proposed in this application will contribute to gaining a better understanding of the molecular and cellular mechanisms of neuroplasticity and ultimately help illuminate the etiology and pathophysiology of schizophrenia. This proposal seeks to devise innovative strategies for assessing the function of genes in the nervous system and to define the mechanisms through which neurons adapt to changes during development and in response to external stimuli. Once our experimental aims have been achieved, it is our long-term goal to apply similar strategies to other severe mental disorders in order to advance our understanding of their causes and to contribute to the discovery of new types of medicines for improving mental health. PUBLIC HEALTH RELEVANCE: The overall goal of our current application is to devise robust, image-based assays of neuroplasticity and an integrated image analysis framework to enable high-throughput, RNAi-based loss-of-function screens in mouse neurons. Genes identified in these high-throughput screens as playing an important role in neuroplasticity will be subject to detailed morphological and functional analyses of their role in regulating neuronal morphology and synaptic transmission.